Hepatitis A Virus Vaccine Inactivated

Introduction

Inactivated virus vaccine.1394755115171 Hepatitis A virus vaccine inactivated contains cell culture-adapted, attenuated hepatitis A virus (HAV) and is used to stimulate active immunity to HAV infection.1394755115171 Commercially available in the US as monovalent vaccines (HepA; Havrix, Vaqta)1171 and in a fixed-combination vaccine with hepatitis B vaccine (HepA-HepB; Twinrix).186

Uses for Hepatitis A Virus Vaccine Inactivated

Prevention of Hepatitis A Virus (HAV) Infection

Prevention of HAV infection in adults, adolescents, and children ≥1 year of age.1322110132171192195196

Although HAV infection may be asymptomatic or relatively mild in many patients, it can result in substantial morbidity and associated health-care costs and work loss (11–22% of patients require hospitalization) and may be associated with fulminant hepatitis and hepatic failure.38596375132203 Overall HAV case-fatality rate in the US is 0.3–0.6%, but increases to about 2% in those ≥40 years of age.192203 HAV is highly contagious (especially during the 2 weeks before onset of symptoms).41621303237425057588591929497110120132203 The virus is transmitted person-to-person, principally through the fecal-oral route.141621303237425057588591929497110120132171203 HAV infection remains one of the most commonly reported vaccine-preventable diseases in travelers.167192

USPHS Advisory Committee on Immunization Practices (ACIP), AAP, and American Academy of Family Physicians (AAFP) recommend that all children be vaccinated against HAV infection at 1 year of age (i.e., 12 through 23 months of age), unless contraindicated.3132192 (See Contraindications under Cautions.)

ACIP, AAP, AAFP, American College of Obstetricians and Gynecologists (ACOG), and American College of Physicians (ACP) also recommend vaccination against HAV for all previously unvaccinated children, adolescents, and adults at high risk of exposure to HAV (see Preexposure Vaccination Against HAV Infection in High-risk Groups under Uses) and for any other unvaccinated individual desiring protection from HAV infection.3132192195196

For internationally adopted children whose immune status is uncertain, vaccinations can be repeated or serologic tests performed to confirm immunity.60167 For HepA vaccine, ACIP states that the simplest approach is to revaccinate according to the US recommended immunization schedule if child is ≥12 months of age.60 (See Dosage and Administration.) Alternatively, test for serologic evidence of susceptibility to HAV.60 (See Pre-and Postvaccination Serologic Testing under Cautions.) When a child is being adopted from a country with high or intermediate HAV endemicity, ACIP states that all previously unvaccinated individuals who anticipate close personal contact with the adoptee during the child’s initial 60 days in the US (e.g., household members, regular babysitters) should receive routine vaccination with HepA vaccine, with the first dose given as soon as adoption is planned (ideally ≥2 weeks before the child’s arrival).209 CDC website () has information regarding which countries have high or intermediate levels of HAV endemicity.167

When vaccination against both HAV and HBV infection is indicated in adults ≥18 years of age, the commercially available fixed-combination vaccine containing HepA vaccine and hepatitis B vaccine (HepA-HepB; Twinrix) can be used.186192 ACIP, AAP, and AAFP state that use of a combination vaccine generally is preferred over separate injections of the equivalent component vaccines;3208 considerations should include provider assessment (e.g., number of injections, vaccine availability, likelihood of improved coverage, likelihood of patient return, storage and cost considerations), patient preference, and potential for adverse effects.3208 However, the HepA-HepB (Twinrix) fixed-combination vaccine should not be used for HAV postexposure prophylaxis.196 (See Use of Fixed Combinations under Cautions.)

Preexposure Vaccination Against HAV Infection in High-risk Groups

Preexposure vaccination in previously unvaccinated children, adolescents, or adults who are or will be at high risk of exposure to HAV or are at high risk of developing fulminant hepatitis and hepatic failure if they become infected with HAV.3132167192195196

ACIP, AAP, AAFP, and others recommend preexposure vaccination in previously unvaccinated children ≥12 months of age who reside in states, counties, or communities where the rate of HAV infection is high and in unvaccinated travelers, unvaccinated household or sexual contacts of an individual with confirmed HAV infection, and unvaccinated individuals at risk because of their occupation or high-risk behavior.1345597476110149171177192195196

If HepA vaccine cannot be used because it is contraindicated or unavailable and short-term protection against HAV is needed, preexposure passive immunization with IGIM is recommended.26323740425974107128132161167196

In states, counties, or communities where the rate of HAV infection is high, ACIP recommends that existing selective preexposure HepA vaccination programs for children 2 through 18 years of age be maintained.192 In such areas, new efforts focused on routine vaccination of all children at 1 year of age should enhance, not replace, ongoing programs directed at a broader population of children.192 In areas without existing selective vaccination programs, catch-up vaccination of unvaccinated children 2 through 18 years of age may be considered.192 Such catch-up vaccination programs may be especially warranted because of rising incidence or ongoing outbreaks of HAV among children or adolescents.192

HIV-infected individuals, especially those with chronic liver disease (including those coinfected with HBV or HCV), should be vaccinated against HAV.197198 ACIP, AAP, CDC, National Institutes of Health (NIH), Infectious Diseases Society of America (IDSA), Pediatric Infectious Diseases Society, and others recommend that HAV-susceptible, HIV-infected adults, adolescents, and children receive HepA vaccine.197198 Consider that the vaccine may be less immunogenic in immunocompromised individuals.60159187192 (See Individuals with Altered Immunocompetence under Cautions.)

Travelers to areas with intermediate to high levels of endemic HAV are at risk of exposure to the disease, and ACIP, CDC, WHO, and others recommend preexposure vaccination against HAV for such individuals.132259639097110167176192196 CDC states vaccination against HAV can be considered in individuals traveling to any destination.167 CDC website () has information regarding which countries have high or intermediate levels of HAV endemicity.167 Risk of acquiring HAV while traveling varies with living conditions, length of stay, and incidence of HAV infection in the area visited.167 Consider that many cases of HAV occur in travelers to developing countries with standard tourist itineraries, accommodations, and food consumption behaviors.167 Ideally, the first dose of HepA vaccine should be administered as soon as travel to countries with high or intermediate HAV endemicity is considered.167196 (See Preexposure Vaccination Against HAV Infection in High-risk Groups under Pediatric Patients and also Adults, in Dosage and Administration.) Alternatively, if the vaccine is contraindicated or cannot be used, passive immunization with a single dose of IGIM may provide protection for up to 3 months.167196 For optimal protection in travelers at greatest risk for HAV (older adults or individuals with altered immunocompetence, chronic liver disease, or other chronic medical condition) who plan to depart in <2 weeks, a dose of IGIM should be given concomitantly with the initial dose of HepA vaccine (at a different site).167 ACIP states that the fixed-combination vaccine containing HepA vaccine and HepB vaccine (HepA-HepB; Twinrix) should not be used for preexposure vaccination in travelers who will depart within 2 weeks.192196 (See Use of Fixed Combinations under Cautions.)

Household and sexual contacts of individuals with confirmed HAV infection are at increased risk of exposure to HAV.21192 Sexually active male adolescents and adults who have sex with men (homosexual, bisexual) should be vaccinated against HAV.2110179192 Primary-care clinicians and those in specialty medical settings should offer the vaccine to such individuals; strategies to increase coverage (e.g., use of standing orders) should be considered.192

Individuals who illicitly use injectable or noninjectable drugs may be at increased risk of exposure to HAV infection and should be vaccinated against HAV.63747697192 Clinicians should obtain a complete history to identify individuals who might benefit from HepA vaccination (e.g., those who use illicit drugs or who are at increased risk for such drug use).192 Clinicians should consider implementing strategies to increase vaccine coverage in these patients (e.g., use of standing orders).192

Workers handling HAV-infected nonhuman primates and workers in contact with live HAV in a research laboratory setting should be vaccinated against HAV.6799108110192 Routine vaccination against HAV is not currently recommended for other occupational groups in the US.192

Individuals with chronic liver disease and those who are awaiting or have undergone liver transplantation should be vaccinated against HAV.132192 Although individuals with chronic liver disease are not at increased risk of acquiring HAV infection, such individuals are at increased risk of severe consequences of HAV infection, including fatal fulminant hepatitis and hepatic failure.1674103110192

Some clinicians recommend that individuals with HBV or HCV infection, autoimmune hepatitis, or primary biliary cirrhosis be vaccinated against HAV.132177 ACIP states that current data do not support routine vaccination of individuals who have chronic HBV or HCV infection but do not have evidence of chronic liver disease.192

Food handlers and restaurant employees may be vaccinated against HAV.84177192 Vaccination may be considered in restaurant employees in areas where state and local health authorities or private employers have determined that such vaccination is indicated to decrease the frequency of HAV evaluations of food handlers and decrease the need for HAV postexposure prophylaxis in restaurant patrons.84177192 Under these circumstances, a record of HepA vaccination should be provided to vaccinated food handlers, those not vaccinated should be informed of the signs and symptoms of HAV infection, and all food handlers should be instructed on food preparation practices that reduce risk of fecal contamination.192 Routine use of HepA vaccine in all food handlers is not economically feasible from a societal or food industry perspective.84177192 Occasionally, vaccination of food handlers may be considered during a community outbreak.110177192

Incarcerated adolescents in correctional facilities located in states with existing HepA vaccination programs for adolescents should receive HepA vaccine.132 Because of the likelihood that adolescents in juvenile correctional systems have indications for the vaccine, other correctional facilities also should consider routine HepA vaccination of all adolescents under their care.132 Test those with signs or symptoms of hepatitis for acute HAV, HBV, and HCV infection.132 Report those with HAV to the local health department and give appropriate postexposure prophylaxis with HepA vaccine to susceptible exposed residents.132

If a community-wide outbreak of HAV occurs, accelerated HepA vaccination programs should be considered.192 A decision to initiate an outbreak-control vaccination program should take into account the feasibility of rapidly vaccinating the target population of children, adolescents, or young adults, and the costs associated with such a program.192 Routine vaccination of children in affected communities should continue in order to maintain high levels of immunity and prevent future epidemics.192

HAV outbreaks in child-care centers have decreased considerably since the implementation of routine childhood immunization against HAV and further decreases are expected.192 ACIP does not recommend routine preexposure vaccination with HepA vaccine for personnel in child-care centers.192 However, HAV postexposure prophylaxis may be indicated if HAV is reported in attendees or staff.196 (See Postexposure Prophylaxis of HAV Infection under Uses.)

ACIP does not recommend routine preexposure vaccination with HepA vaccine in hospitals or schools and institutions for the developmentally disabled because the frequency of outbreaks in these institutions is not high enough to warrant such recommendations.192 Outbreaks involving student-to-student transmission in primary and secondary schools are rare in developed countries, but outbreaks have been documented;32132161192 in developing countries, outbreaks among children in primary schools are more common.7151161 If an epidemiologic investigation indicates HAV transmission has occurred among students in a school or among patients or between patients and staff in a hospital, HAV postexposure prophylaxis should be administered to individuals who have close contact with index patients.107132192196 (See Postexposure Prophylaxis of HAV Infection under Uses.)

ACIP and Hospital Infection Control Practices Advisory Committee (HICPAC) state that routine preexposure vaccination with HepA vaccine or routine use of HAV postexposure prophylaxis in health-care personnel providing care to patients with HAV infection is not indicated.178192 Instead, hygienic practices should be emphasized and health-care personnel should be made aware of the risk of exposure to HAV and precautions regarding direct contact with potentially infective materials.178192 In documented outbreaks of HAV infection, HAV postexposure prophylaxis may be indicated in health-care workers and others who have close contact with the infected individuals.178 (See Postexposure Prophylaxis of HAV Infection under Uses.) The usefulness of HepA vaccine in controlling outbreaks in health-care settings has not been investigated.178

Postexposure Prophylaxis of HAV Infection

The choice of active immunization with HepA vaccine and/or passive immunization with IGIM for postexposure prophylaxis should take into account the magnitude of risk associated with the exposure and characteristics of the patient that may be associated with more severe manifestations of HAV (e.g., older age, chronic liver disease).132178179192196

Although IGIM was traditionally the recommended regimen for HAV postexposure prophylaxis since it is 80–90% effective if administered within 2 weeks of exposure,196 there is some evidence that monovalent HepA vaccine administered within 2 weeks of exposure may be as effective as IGIM in healthy individuals 1–40 years of age.196199 The vaccine also offers certain advantages over IGIM (e.g., induces active immunity and longer protection, more readily available, easier to administer, greater patient acceptance).196199

For HAV postexposure prophylaxis in healthy individuals 12 months to 40 years of age, ACIP prefers use of monovalent HepA vaccine.196 In adults >40 years of age, ACIP prefers use of IGIM since data not available to date regarding efficacy of the vaccine for postexposure prophylaxis in this age group and these individuals are at risk of more severe manifestations of HAV; the vaccine can be used if IGIM cannot be obtained.196 IGIM should be used for HAV postexposure prophylaxis in children <12 months of age, immunocompromised individuals, individuals with chronic liver disease, and whenever the vaccine is contraindicated.196

In those individuals in whom IGIM is preferred for HAV postexposure prophylaxis, a dose of HepA vaccine should be given simultaneously (using different syringes and different injection sites) if the vaccine is indicated for other reasons (e.g., catch-up vaccination, preexposure vaccination in high-risk groups) and is not contraindicated.196 If a dose of HepA vaccine is used with or without IGIM for HAV postexposure prophylaxis, a second (booster) dose of the vaccine should be administered according to the usually recommended schedule to ensure long-term protection.192196 (See Dosage under Dosage and Administration.)

Monovalent HepA vaccine (Havrix, Vaqta) should be used when active immunization is indicated for HAV postexposure prophylaxis.196 Data not available to date regarding efficacy of the fixed-combination vaccine containing HepA vaccine and HepB vaccine (HepA-HepB; Twinrix) for postexposure prophylaxis.196 (See Use of Fixed Combinations under Cautions.)

If HAV postexposure prophylaxis is indicated, administer as soon as possible (within 2 weeks of exposure).192196 Data not available regarding efficacy of HAV postexposure prophylaxis administered >2 weeks after exposure.196

HAV postexposure prophylaxis is indicated in all previously unvaccinated individuals who have had household or sexual contact (within the last 2 weeks) with an individual with serologically confirmed HAV.196 Also consider HAV postexposure prophylaxis for individuals exposed (within the last 2 weeks) through other types of ongoing, close personal contact (e.g., regular babysitting).196

Contacts who have shared illicit drugs (within the last 2 weeks) with an individual with serologically confirmed HAV should receive HAV postexposure prophylaxis.196

Administer HAV postexposure prophylaxis to all previously unvaccinated staff and attendees of child-care centers or homes if ≥1 case of HAV is recognized in children or employees or if HAV is recognized in ≥2 households of center attendees (within the last 2 weeks).196 In centers that do not provide care to children who wear diapers, HAV postexposure prophylaxis is indicated only in classroom contacts of the index patient.196 If an outbreak occurs (i.e., HAV in ≥3 families), HAV postexposure prophylaxis should also be considered for members of households that have diapered children attending the center.196

If HAV is diagnosed in a food handler, ACIP recommends HAV postexposure prophylaxis (within 2 weeks) for other food handlers at the same establishment.196 Because common-source transmission to patrons is unlikely, HAV postexposure prophylaxis is not usually indicated for restaurant patrons, but may be considered if the food handler directly handled uncooked or cooked food and had diarrhea or poor hygienic practices and if patrons can be identified and treated within 2 weeks of exposure.196 Settings where repeated HAV exposure might have occurred (e.g., institutional cafeterias) warrant stronger consideration of postexposure prophylaxis for patrons.196

When an individual with HAV is admitted to a hospital, health-care personnel do not need to receive routine HAV postexposure prophylaxis; careful hygienic practices should be emphasized in such situations.196

If an epidemiologic investigation indicates that HAV transmission has occurred among students in a school or among hospital patients and/or hospital staff, ACIP recommends HAV postexposure prophylaxis in individuals who have close contact with index patients.196

Routine HAV postexposure prophylaxis is not indicated when a single HAV case occurs in an elementary or secondary school or an office or other work setting and the source case is outside the school or work setting.196

HAV postexposure prophylaxis is not usually indicated after a common-source HAV outbreak if cases have begun to occur because the 2-week period when such prophylaxis is known to be effective will have been exceeded.196

Shake vaccine well immediately prior to administration to provide a uniform, slightly turbid, white, suspension.1171186200 Discard vaccine if there are cracks in the vial or syringe or if it contains particulates, appears discolored, or cannot be resuspended with thorough agitation.1171200

Do not dilute.1186 Do not mix with any other vaccine or solution.160171186

To ensure delivery into muscle, IM injections should be made at a 90° angle to the skin60 using a needle length appropriate for the individual’s age and body mass, thickness of adipose tissue and muscle at the injection site, and injection technique.60206207 Consider anatomic variability, especially in the deltoid; use clinical judgment to avoid inadvertent underpenetration or overpenetration of muscle.206207

For adults, administer IM into the deltoid muscle.160 For children 1–2 years of age, IM injections should preferably be administered into the anterolateral thigh;160 deltoid muscle is an alternative if muscle mass is adequate.60 For children and adolescents 3–18 years of age, deltoid muscle is preferred,160 although anterolateral thigh is an alternative.60

Generally do not administer vaccines into buttock muscle in children because of potential for injection-associated injury to sciatic nerve.60 In addition, studies in adults indicate suboptimal immunologic response may occur if HepA vaccine is injected into gluteal muscle.160

Although some experts state that aspiration (i.e., pulling back on the syringe plunger after needle insertion and before injection) can be performed to ensure that a blood vessel has not been entered, ACIP and AAP state this procedure is not required because large blood vessels are not present at recommended IM injection sites.60132

Since syncope may occur following vaccination, observe vaccinees for approximately 15 minutes after the dose.60 Syncope occurs most frequently in adolescents and young adults.60 If syncope occurs, observe patient until symptoms resolve.60

May be given simultaneously with IGIM (using different syringes and different injection sites) when passive immunization is considered necessary in addition to active immunization with the vaccine (e.g., in travelers who will depart within 2 weeks).160132171192196 (See Interactions.)

May be given simultaneously with other age-appropriate vaccines during the same health-care visit (using different syringes and different injection sites).60132192 (See Interactions.)

When multiple vaccines are administered during a single health-care visit, each vaccine should be given with a different syringe and at different injection sites.60 Separate injection sites by at least 1 inch (if anatomically feasible) to allow appropriate attribution of any local adverse effects that may occur.60 If multiple vaccines must be given into a single limb, the deltoid may be used in older children and adults, but the thigh is preferred in younger children.60

Dosage

Dose and dosing schedule vary according to the individual’s age and specific vaccine administered.1171186Follow dosage recommendations for the specific preparation used.192

Whenever possible, the HepA monovalent vaccine used for the initial dose should be used for subsequent doses in the same individual.192 However, ACIP and AAP state that the currently available monovalent formulations may be considered interchangeable.60132192

For both monovalent vaccines, the minimum interval between the first and second dose is 6 months.13171192 Dosage for the second (booster) dose should be based on the individual’s age at the time the second dose is given.203 Although only limited data are available regarding the immune response to delayed administration of the second dose,192 some experts state it is not necessary to repeat the first dose if the interval between the first and second dose extends beyond 18 months.203

When vaccination against both HAV and HBV infection is indicated in adults ≥18 years of age, the commercially available fixed-combination vaccine containing HepA vaccine and HepB vaccine (HepA-HepB; Twinrix) can be used.186192

Pediatric Patients

Prevention of Hepatitis A Virus (HAV) Infection

Children and Adolescents 12 Months through 18 Years of Age (Havrix)

ACIP, AAP, and AAFP recommend that the initial dose be given routinely to all children at 1 year of age (i.e., 12 through 23 months of age) and that the second dose be given at least 6 months after the initial dose.3

Children not fully vaccinated by 2 years of age can be vaccinated at subsequent health-care visits.3 ACIP recommends that catch-up vaccination be considered for children 2 through 18 years of age in areas without existing selective preexposure HepA vaccination programs.192

If a different HepA vaccine (e.g., Vaqta) was used for the initial dose, a booster dose of Havrix may be given 6–18 months after the initial dose of the other vaccine.192 However, whenever possible, the formulation chosen for the initial dose should be used for the booster dose in the same individual.192

Duration of immunity and need for subsequent doses after the initial dose and additional (booster) dose not fully determined.1267233341464974767784145149150155192 (See Duration of Immunity under Cautions.) Subsequent booster doses not recommended.192

ACIP, AAP, and AAFP recommend that the initial dose be given routinely to all children at 1 year of age (i.e., 12 through 23 months of age) and that the second dose be given at least 6 months after the initial dose.3

Children not fully vaccinated by 2 years of age can be vaccinated at subsequent health-care visits.3 ACIP recommends that catch-up vaccination be considered for children 2 through 18 years of age in areas without existing selective preexposure HepA vaccination programs.192

If a different HepA vaccine (e.g., Havrix) was used for the initial dose, a booster dose of Vaqta may be given 6–12 months after the initial dose of the other vaccine.171192 However, whenever possible, the formulation chosen for the initial dose should be used for the booster dose in the same individual.192

Duration of protection and need for subsequent doses after the initial dose and second (booster) dose not fully determined.267233341464974767784145149150155171192 (See Duration of Immunity under Cautions.) Subsequent booster doses not recommended.192

Preexposure Vaccination Against HAV Infection in High-risk Groups

Children and Adolescents 12 Months through 18 Years of Age (Havrix or Vaqta)

IM

Primary immunization with the usually recommended age-appropriate initial and second (booster) doses before an expected exposure to HAV ensures the highest level of protection.1148158171192196 (See Prevention of Hepatitis A Virus (HAV) Infection under Dosage and Administration.) Those who have received at least 1 dose given 1 month prior to an exposure probably will be protected.167192196

For individuals who plan to travel or work in areas with intermediate to high levels of endemic HAV (see Preexposure Vaccination Against HAV Infection in High-risk Groups under Uses), give first vaccine dose as soon as travel is considered.167196 For most healthy children, a single dose will provide adequate protection regardless of the scheduled departure date.167196 To ensure protection in immunocompromised individuals or those with chronic liver disease or other chronic medical conditions who plan to depart within 2 weeks, give initial vaccine dose and simultaneously (using a different syringe and different injection site) give a single dose of IGIM (0.02 mL/kg).167196

Children and Adolescents 12 Months through 18 Years of Age (Havrix or Vaqta)

IM

Give an age-appropriate dose of vaccine alone or in conjunction with a dose of IGIM (0.02 mL/kg) as soon as possible.196 Efficacy of HAV postexposure prophylaxis not established if given >2 weeks after exposure.196 (See Postexposure Prophylaxis of HAV Infection under Uses.)

In previously unvaccinated individuals, give primary immunization with the usually recommended age-appropriate initial and second (booster) doses of the vaccine.1107111128171192 (See Prevention of Hepatitis A Virus (HAV) Infection under Dosage and Administration.) The first vaccine dose can be administered simultaneously with IGIM (using different syringes and different injection sites).1107111128171192

Individuals who have received at least 1 vaccine dose at least 1 month prior to the current HAV exposure do not need to receive postexposure prophylaxis with IGIM.179192

Adults

Prevention of Hepatitis A Virus (HAV) Infection

Adults ≥19 Years of Age (Havrix)

If a different HepA vaccine (e.g., Vaqta) was used for the initial dose, a booster dose of Havrix may be given 6–12 months after the initial dose of the other vaccine.192 However, whenever possible, the formulation chosen for the initial dose should be used for the booster dose in the same individual.132192

Duration of protection and need for subsequent doses after the initial dose and second (booster) dose not fully determined.1267233341464974767784145149150155171192 (See Duration of Immunity under Cautions.) Subsequent booster doses not recommended.192

If a different HepA vaccine (e.g., Havrix) was used for the initial dose, a booster dose of Vaqta may be given 6–12 months after the initial dose of the other vaccine.171192 However, whenever possible, the formulation chosen for the initial dose should be used for subsequent doses in the same individual.192

Duration of protection and need for subsequent doses after the initial primary dose and second (booster) dose not fully determined.267233341464974767784145149150155192 (See Duration of Immunity under Cautions.) Subsequent booster doses not recommended.192

Adults ≥18 Years of Age (HepA-HepB; Twinrix)

IM

Primary immunization consists of a series of 3 doses.186 Each 1-mL dose contains at least 720 units of HAV antigen and 20 mcg of hepatitis B surface antigen (HBsAg).186

For primary immunization in most patients, give initial dose on a selected date and give second and third doses at 1 and 6 months, respectively, after initial dose.186

Alternatively, if an accelerated dosing schedule is needed, give initial dose on a selected date and give second and third doses at 7 and 21–30 days, respectively, after initial dose; also give a fourth (booster) dose at 12 months after initial dose.186

Duration of immunity and need for subsequent doses after the recommended vaccine series not fully determined.186 (See Duration of Immunity under Cautions.) Booster dose is indicated if an accelerated dosing schedule is used, but booster doses not recommended following the usually recommended 3-dose regimen.186

Preexposure Vaccination Against HAV Infection in High-risk Groups

Adults≥19 Years of Age (Havrix or Vaqta)

IM

Primary immunization with the usually recommended initial and second (booster) doses before an expected exposure to HAV ensures the highest level of protection.1148158171192196 (See Prevention of Hepatitis A Virus (HAV) Infection under Dosage and Administration.) Those who have received at least 1 dose given 1 month prior to an exposure probably will be protected.167192196

For individuals who plan to travel or work in areas with intermediate to high levels of endemic HAV (see Preexposure Vaccination Against HAV Infection in High-risk Groups under Uses), give first vaccine dose as soon as travel is considered.167196 For most healthy adults ≤40 years of age, a single vaccine dose will provide adequate protection regardless of the scheduled departure date.167196 To ensure protection in adults >40 years of age, immunocompromised individuals, or those with chronic liver disease or other chronic medical conditions who plan to depart within 2 weeks, give initial vaccine dose and simultaneously (using a different syringe and different injection site) give a single dose of IGIM (0.02 mL/kg).167196

Adults ≥19 Years of Age (Havrix or Vaqta)

IM

Adults ≤40 years of age: Give an age-appropriate dose of vaccine alone or in conjunction with IGIM (0.02 mL/kg) as soon as possible.196 Efficacy of HAV postexposure prophylaxis not established if given >2 weeks after exposure.196 (See Postexposure Prophylaxis of HAV Infection under Uses.)

Adults >40 years of age: An age-appropriate dose of vaccine can be given, but individuals in this age group should receive IGIM for postexposure prophylaxis.196

In previously unvaccinated individuals, give primary immunization with the usually recommended age-appropriate initial and second (booster) doses of the vaccine.1107111128171192 (See Prevention of Hepatitis A Virus (HAV) Infection under Dosage and Administration.) The first vaccine dose can be administered simultaneously with IGIM (using different syringes and different injection sites).1107111128171192

Individuals who have received at least 1 vaccine dose at least 1 month prior to the current HAV exposure do not need to receive postexposure prophylaxis with IGIM.179192

Warnings/Precautions

Sensitivity Reactions

Hypersensitivity Reactions

Although risk of sensitivity reactions appears to be low,7 anaphylaxis and anaphylactoid manifestations have been reported rarely.12192 Bronchoconstriction,171 asthma,171 wheezing,171 and serum sickness-like syndrome1 also reported rarely.

Take all known precautions to prevent adverse reactions, including a review of the patient’s history with respect to possible hypersensitivity to the vaccine or similar vaccines.186

Epinephrine and other appropriate agents should be readily available in case anaphylaxis or an anaphylactoid reaction occurs.160171186 If a hypersensitivity reaction occurs, immediately institute appropriate therapy as indicated.60171186

Do not administer additional vaccine doses to individuals who had a hypersensitivity reaction to a previous dose.160171

Neomycin Allergy

Havrix and Twinrix contains trace amounts of neomycin sulfate.1186 Manufacturers state these vaccines contraindicated in individuals hypersensitive to neomycin.1186

Neomycin allergy usually results in delayed-type (cell-mediated) hypersensitivity reactions manifested as contact dermatitis.60132 ACIP and AAP state that vaccines containing trace amounts of neomycin should not be used in individuals with a history of anaphylactic reaction to neomycin, but use of such vaccines may be considered in those with a history of delayed-type neomycin hypersensitivity if benefits of vaccination outweigh risks.60132

Some individuals may be hypersensitive to natural latex proteins.60189190191 Take appropriate precautions if these preparations are administered to individuals with a history of latex sensitivity.60189190191

General Precautions

Limitations of Vaccine Effectiveness

May not protect all vaccine recipients against HAV infection.1171

Individuals who have received at least 1 dose of vaccine given 1 month prior to HAV exposure probably will be protected.167192 Use of both an initial and second (booster) dose given ≥6 months later ensures the highest level of protection.1148158171192

Consider possibility that unrecognized HAV infection may be present in some individuals at the time of vaccination (infection has an incubation period of 15–50 days) and that the vaccine may not prevent infection in such individuals.1171

May not prevent infection in individuals who do not achieve protective antibody titers; the minimum titer needed to confer HAV immunity has not been established.1171 (See Actions.)

Travelers to areas with intermediate to high levels of endemic HAV who are >40 years of age, immunocompromised, or have chronic liver disease or other chronic medical conditions who receive preexposure vaccination with a dose of monovalent HepA vaccine given within 2 weeks of departure should also receive passive immunization with a dose of IGIM to ensure optimal protection.196

ACIP states that the fixed-combination vaccine containing HepA vaccine and HepB vaccine (HepA-HepB; Twinrix) should not be used for preexposure vaccination in travelers who will depart within 2 weeks and should not be used for postexposure prophylaxis against HAV.196 (See Use of Fixed Combinations under Cautions.)

Duration of Immunity

Duration of protection and need for subsequent doses after the initial dose and second (booster) dose of HepA vaccine not fully determined.1267233341464974767784132145149150155167171192

HepA vaccine has only been available in the US since 1995–1996.192203 Data to date indicate that vaccine-induced antibodies are detectable for at least 5–12 years,33132167192 but decline over time.62192 It has been estimated that protective levels of anti-HAV may persist for ≥20–25 years after vaccination.262132167192203 Additional study is necessary before recommendations can be made regarding the need, if any, for additional booster doses of the vaccine.171192

Individuals with Altered Immunocompetence

May be administered to individuals immunosuppressed as the result of disease or immunosuppressive therapy.60159167192 Consider possibility that the immune response to the vaccine and efficacy may be reduced in these individuals.11460132159167171192

Recommendations regarding use in HIV-infected adults, adolescents, and children are the same as those for individuals who are not infected with HIV.197198 Because HIV-infected individuals with chronic liver disease (including those coinfected with HBV or HCV) are at risk of fulminant hepatic failure if they acquire HAV, ACIP, AAP, CDC, NIH, IDSA, Pediatric Infectious Diseases Society, and others recommend that such individuals receive HepA vaccine.197198 Response to the vaccine may be reduced in those with CD4+ T-cell counts <200 cells/mm3; some experts suggest delaying vaccination until patient is receiving antiretroviral therapy and CD4+ T-cell count is >200 cells/mm3.197 Assess antibody response 1 month after vaccination; revaccinate nonresponders.197

Concomitant Illness

A decision to administer or delay vaccination in an individual with a current or recent febrile illness depends on the severity of symptoms and etiology of the illness.60

Some manufacturers state the vaccine may be given to individuals with acute infection or febrile illness if withholding the vaccine poses greater risk to the patient.171

ACIP states that minor acute illness, such as mild diarrhea or mild upper respiratory tract infection (with or without fever) generally does not preclude vaccination, but vaccination should be deferred in individuals with moderate or severe acute illness (with or without fever).60

Individuals with Bleeding Disorders

Because bleeding may occur following IM administration in individuals with thrombocytopenia or a bleeding disorder (e.g., hemophilia) or in those receiving anticoagulant therapy, use caution in such individuals.1860169171186

ACIP states that vaccines may be given IM to individuals who have bleeding disorders or are receiving anticoagulant therapy if a clinician familiar with the patient’s bleeding risk determines that the preparation can be administered with reasonable safety.60 In these cases, use a fine needle (23 gauge) to administer the vaccine and apply firm pressure to the injection site (without rubbing) for ≥2 minutes.1860 If patient is receiving antihemophilia therapy, administer the IM vaccine shortly after a scheduled dose of such therapy.1860

Advise individual and/or their family about the risk of hematoma from IM injections.1860171

Pre- and Postvaccination Serologic Testing

Prevaccination testing for susceptibility to HAV is not usually indicated unless such testing would be less costly than unnecessarily vaccinating an individual who is already immune.140145149167192203 Natural HAV infection produces lifelong immunity and high rates of HAV seropositivity are present in some populations for whom HepA vaccination is recommended.192203 However, vaccination of an individual with preexisting immunity is not associated with any unusual risk.167192203

Prevaccination serologic testing is not indicated before routine or catch-up vaccination of children or most adolescents.132192203

Prevaccination serologic testing can be considered for adults who were born in or resided for extensive periods in geographic areas with intermediate or high levels of endemic HAV (e.g., Central and South America, Africa, Asia), older adolescents and adults in populations or groups with a high prevalence of infection (e.g., Native Americans, Alaska Natives, Hispanics), adults >40 years of age, adult men who have sex with men, and adults who illicitly use injectable or noninjectable drugs.140141142144167192203

If prevaccination testing is indicated, commercially available tests that measure total anti-HAV (i.e., both IgG and IgM anti-HAV) are used.791123374257768487140141142192203 A positive result indicates the individual is immune as the result of past infection or vaccination.203

Routine screening of contacts for preexisting HAV immunity prior to administration of HAV postexposure prophylaxis is not recommended.107132192 However, because HAV infection cannot be diagnosed reliably by clinical presentation alone, serologic confirmation of HAV in the index case is recommended before HAV postexposure prophylaxis in contacts.4286132192

Postvaccination serologic testing to confirm HAV immunity is not necessary in most individuals because of the high rate of vaccine response among adults and children.109142145167192203 When HepA vaccine is used in HIV-infected individuals, some experts recommend assessing antibody response 1 month after vaccination and revaccinating nonresponders.197 The National Hemophilia Foundation’s Medical and Scientific Advisory Council (MASAC) strongly recommends such testing following HepA vaccination in adults and children with hemophilia.18

Use of Fixed Combinations

Whenever the fixed-combination vaccine containing HepA vaccine and HepB vaccine (HepA-HepB; Twinrix) is used, consider the contraindications and precautions associated with both antigens.186

Although an accelerated dosing schedule of the fixed-combination vaccine containing HepA vaccine and HepB vaccine (HepA-HepB; Twinrix) can be used when necessary (e.g., for travelers), a booster dose is necessary 1 year later.167186 (See Adults ≥18 Years of Age (HepA-HepB; Twinrix) under Dosage.) The ACIP states that HepA-HepB (Twinrix) should not be used for preexposure vaccination of travelers who will depart within 2 weeks after receipt of the vaccine;196 the vaccine contains less HAV antigen and data are not available regarding efficacy in this situation.192196

Fixed-combination vaccine containing HepA vaccine and HepB vaccine (HepA-HepB; Twinrix) should not be used for HAV postexposure prophylaxis;196 the vaccine contains less HAV antigen and data are not available regarding efficacy in this situation.192196

Improper Storage and Handling

Improper storage or handling of vaccines may result in loss of vaccine potency and reduced immune response in vaccinees.60200

Inspect all vaccines upon delivery and monitor during storage to ensure that the appropriate temperature is maintained.60200

Do not administer HepA vaccine that has been mishandled or has not been stored at the recommended temperature.60200 (See Storage under Stability.) If there are concerns about mishandling, contact the manufacturer or state or local health departments for guidance on whether the vaccine is usable.200

Specific Populations

Pregnancy

Havrix or Vaqta: Category C.1171

Twinrix: Category C.186 Pregnancy registry at 888-452-9622.186 Clinicians or vaccinees should report any exposure to the vaccine that occurs during pregnancy.186

Manufacturers state HepA vaccine may be used during pregnancy if clearly needed.1171

Because HepA vaccine is an inactivated vaccine, the theoretical risk to the fetus is expected to be low,60167 ACIP, AAP, AAFP, ACOG, and ACP state the vaccine may be used in pregnant women when indicated for preexposure vaccination in high-risk groups (including travelers) or for postexposure prophylaxis.195201

If only short-term protection against HAV infection is needed during pregnancy, consider passive immunization with IGIM as an alternative to active immunization with HepA vaccine.107128132192

Lactation

Use with caution in nursing women.160171186

Because inactivated vaccines do not multiply within the body, they should not pose any unusual problems for lactating women or their infants.60167

Pediatric Use

Havrix or Vaqta: Safety and efficacy not established in children <12 months of age.1171 In young infants, passively acquired maternal anti-HAV antibody may interfere with the active immune response to HepA vaccine.188192 Passively acquired antibody declines to undetectable levels in most infants by 1 year of age, and the vaccine is highly immunogenic in children who begin the vaccine series after 1 year of age (regardless of maternal anti-HAV status).192

Twinrix: Safety and efficacy not established in children <18 years of age.186

Geriatric Use

Havrix : Clinical studies did not include sufficient numbers of patients ≥65 years of age to determine whether geriatric patients respond differently from younger patients; other clinical experience has not revealed evidence of age-related differences.1

Vaqta: Clinical studies and postmarketing safety studies included individuals ≥65 years of age.171 No overall differences in immunogenicity or safety were observed between geriatric and younger patients and there has been no evidence of age-related differences, but the possibility that some older patients may exhibit increased sensitivity to the vaccine cannot be ruled out.171

Twinrix: Clinical studies did not include sufficient numbers of individuals ≥65 years of age to determine whether geriatric individuals respond differently than younger adults.186

Twinrix: Adverse effects similar to those reported when monovalent HepA vaccine and monovalent HepB vaccine are administered alone or concurrently at different sites.186

Interactions for Hepatitis A Virus Vaccine Inactivated

Other Vaccines

Although specific studies may not be available evaluating concurrent administration with each antigen, simultaneous administration with other age-appropriate vaccines, including live virus vaccines, toxoids, or inactivated or recombinant vaccines, during the same health-care visit is not expected to affect immunologic responses or adverse reactions to any of the preparations.60132192 Immunization with HepA vaccine can be integrated with immunization against diphtheria, tetanus, pertussis, Haemophilus influenzae type b (Hib), hepatitis B, influenza, measles, mumps, rubella, meningococcal disease, pneumococcal disease, poliomyelitis, and varicella.3132192 However, each vaccine should be administered using a different syringe and different injection site.1132171

Specific Drugs and Laboratory Tests

Drug or Test

Interaction

Comments

Anti-infective agents

Concurrent use of anti-infectives generally does not affect the immune response to inactivated vaccines, including HepA vaccine or fixed-combination vaccine containing HepA vaccine and HepB vaccine (Twinrix)60

May be administered concurrently with DTaP (using different syringes and different injection sites)1

Haemophilus b (Hib) vaccine

Concomitant administration of Havrix HepA vaccine with Hib polysaccharide conjugate (tetanus toxoid conjugate) vaccine (PRP-T; OmniHIB [not commercially available in the US]) and DTaP at different sites in children 15–18 months of age did not affect the immune response to Havrix or Hib vaccine;1 there was a higher incidence of some adverse effects (e.g., irritability, drowsiness, loss of appetite) in those who received Havrix concurrently with PRP-T and DTaP than in those who received Havrix alone1

May be given concurrently (using different syringes and different injection sites)160132

Hepatitis B (HepB) vaccine

Simultaneous administration of monovalent HepA vaccine and monovalent HepB vaccine does not interfere with the immune response or increase the frequency of adverse effects to either vaccine104145146192

A 3-dose series of the fixed-combination vaccine containing HepA vaccine and HepB vaccine (Twinrix) results in immune responses and adverse effects similar to those reported when a 2-dose series of monovalent HepA vaccine (Havrix) and a 3-dose series of monovalent HepB vaccine (Engerix-B) is given concurrently in opposite arms186

Monovalent HepA vaccine and monovalent HepB vaccine may be given simultaneously (using different syringes and different injection sites)192

Alternatively, may be given simultaneously as the fixed-combination vaccine containing HepA vaccine and HepB vaccine (Twinrix)186192

Immune globulin (IGIM)

Anti-HAV passively acquired from IGIM may interfere with the active antibody response to HepA vaccine;353658111125192 although reduced titers of anti-HAV may occur in adults who receive IGIM and the vaccine concurrently, the seroconversion rate is not affected13658132192

It has been suggested that because vaccine-induced titers generally are higher than antibody levels considered protective, the reduced immunogenicity associated with passively acquired anti-HAV may not be clinically important353658111125192

ACIP states that development of a protective antibody response should not be impaired if HepA vaccine is administered concurrently or at any interval before or after administration of an antibody-containing preparation60

If combined active immunization with HepA vaccine and passive immunization with IGIM is used (e.g., for postexposure prophylaxis), the first dose of vaccine should be administered simultaneously with IGIM (using different syringes and different injection sites)160107111128167171192

Vaccines generally should be administered 2 weeks prior to initiation of immunosuppressive therapy or deferred until at least 3 months after such therapy is discontinued1460

Additional doses of HepA vaccine may be required to induce protective levels of HAV antibody160171

Measles, mumps, and rubella vaccine (MMR)

Concomitant administration of HepA vaccine and MMR (at different sites) did not affect immune response to the measles, mumps, rubella, or hepA antigens171

May be given simultaneously (using different syringes and different injection sites)132171

Pneumococcal vaccine

Pneumococcal 7-valent conjugate vaccine (PCV7; Prevnar): Concomitant administration with Havrix in children 15 months of age did not affect the immune response to either vaccine1

May be given simultaneously (using different syringes and different injection sites)160132

Pneumococcal 7-valent conjugate vaccine (PCV7; Prevnar): Manufacturer states Havrix may be administered simultaneously with the fourth dose of Prevnar (using different syringes and different injection sites)1

Tests to diagnose HAV infection

Individuals who have received HepA vaccine and are being evaluated for suspected HAV infection using serologic tests that detect IgM anti-HAV may have a positive test result in the absence of infection, especially if the test is performed within 2–3 weeks after vaccine administration;172192 only 1% of vaccinees had detectable IgM anti-HAV 1 month after vaccination172

Typhoid vaccine

Parenteral inactivated typhoid vaccine (Typhim Vi): Concomitant administration with HepA vaccine does not appear to affect the immune response or adverse reactions to either vaccine171205

May be given simultaneously (using different syringes and different injection sites)171

Varicella vaccine

Monovalent varicella vaccine (Varivax): Concomitant administration with HepA vaccine and with MMR at different sites did not affect antibody response to HepA vaccine; immunogenicity data insufficient to date to assess response to varicella vaccine171

Yellow fever vaccine

HepA vaccine and yellow fever vaccine may be given concomitantly (using different syringes and different injection sites)171204

Stability

Storage

Parenteral

Injectable Suspension, for IM Use

Havrix and Vaqta: 2–8°C.160171200 Do not freeze;160171200 if freezing occurs, discard vaccine.1

Twinrix: 2–8°C.186 Do not freeze;186 if freezing occurs, discard vaccine.186

Havrix, Vaqta, and Twinrix do not contain thimerosal or any other preservatives.1171186

HepA vaccine is commercially available as monovalent vaccine (Havrix, Vaqta)1171 and as a fixed-combination vaccine containing both HAV and HBV antigens (HepA-HepB; Twinrix).186

Havrix and Vaqta contain different HAV antigens,1171192 but are considered to have equivalent immunogenicity when administered in recommended dosages.60132192 Twinrix contains the same HAV antigen as Havrix (but in a lower concentration) and the same HBV antigen as Engerix-B HepB vaccine.186192

HepA vaccine is highly immunogenic in most adults, adolescents, and children ≥1 year of age.178910111233353647484962112150151152153154155156157171192203 Anti-HAV is detectable in most individuals within 2 weeks after a single dose of monovalent HepA vaccine; protection may not be complete until 4 weeks after the dose.192 At least 94% of adults, adolescents, and children develop protective antibody within 4 weeks after a single dose; almost 100% seroconvert after 2 vaccine doses.192203

In a study in adults with chronic liver disease (chronic HBV, chronic HCV, alcoholic cirrhosis, autoimmune hepatitis, chronic hepatitis/cryptogenic cirrhosis, hemochromatosis primary biliary cirrhosis, primary sclerosing cholangitis), seroconversion rates after first dose of HepA vaccine were lower than those in healthy adults;1 however, seroconversion rates 1 month after the second (booster) dose were similar in both groups.1

Although vaccine-induced anti-HAV levels are lower than those induced by natural infection,192 protection against HAV is virtually complete in those who develop anti-HAV after immunization.4789101112132232334748496263192

The principal mode of transmission of HAV is enteric (i.e., through fecal contamination and oral ingestion), most commonly from person to person, particularly from children to adults.46162132374250598591929497120132167171192203 HAV also can be spread by infected food handlers,61629192 sewage-contaminated drinking water,137 raw or undercooked shellfish (e.g., clams, mussels, oysters) from contaminated waters,162891136 uncooked contaminated foods (e.g. fruits, vegetables),167192 poor hygienic conditions during travel to certain areas of the world,1622262790167192 closed living conditions (e.g., among institutionalized children and adults),25 health-care settings,192 and parenteral transmission (e.g., transfusions of blood or plasma-derived preparations from HAV-infected individuals, sharing needles with infected individuals).1162127324263929497138139165166171192

Natural HAV infection results in lifelong immunity.203 Because of HepA vaccination programs, the rate of HAV infection has declined sharply in the US during the last decade, especially among children.192203 However, an increasingly larger proportion of older Americans are susceptible to the disease (i.e., at an age when the risk of fulminant hepatitis is increased).93138577592192

The minimum titer of anti-HAV conferring protection against HAV has not been established.1233107128192 ACIP states that any level of anti-HAV detected by commercially available assays can be considered protective; however, individuals who are anti-HAV negative may still have protective levels of anti-HAV depending on the lower limits of detection of the assay.109192

Advice to Patients

Provide copy of manufacturer’s patient information to the patient and/or patient’s parent or guardian.1171186 Prior to administration of each vaccine dose, also provide a copy of the appropriate CDC Vaccine Information Statement (VIS) to the patient or patient’s legal representative as required by the National Childhood Vaccine Injury Act (VISs are available at ).192202

Advise patient and/or patient’s parent or guardian of the risks and benefits of vaccination with HepA vaccine.1171186

Importance of receiving both the initial dose and second (booster) dose to ensure the highest level of protection against HAV.1171192

Importance of informing clinicians if any adverse reactions (e.g., hypersensitivity reactions) occur.1171186 Clinicians or individuals can report any adverse reactions that occur following vaccination to Vaccine Adverse Event Reporting System (VAERS) at 800-822-7967 or .1171

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1171186

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1171186

Importance of informing patients of other important precautionary information.1171186 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

3. Advisory Committee on Immunization Practices of the Centers for Disease Control and Prevention, American Academy of Pediatrics, and American Academy of Family Physicians. Recommended immunization schedules for persons aged 0 through 18 years—United States, 2010; 59.

172. Centers for Disease Control and Prevention. Prevention of hepatitis A through active or passive immunization: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 1999; 48(RR-12):1-37.

192. Centers for Disease Control and Prevention. Prevention of hepatitis A through active or passive immunization: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2006; 55(RR-7):1-23.

208. Centers for Disease Control and Prevention. ACIP provisional recommendations for the use of combination vaccines. August 28, 2009. From CDC website ().

209. Centers for Disease Control and Prevention (CDC), Advisory Committee on Immunization Practices. Updated recommendations from the Advisory Committee on Immunization Practices (ACIP) for use of hepatitis A vaccine in close contacts of newly arriving international adoptees. MMWR Morb Mortal Wkly Rep. 2009; 58:1006-7. [PubMed 19763077]